tbuckley/cabot-search huggingface dataset:
Cuts to local government spending, multimorbidity and health-related quality of life: A longitudinal ecological study in England
Authors: Jonathan Stokes, Peter Bower, Bruce Guthrie, Stewart W. Mercer, Nigel Rice, Andrew M. Ryan, Matt Sutton
Journal: The Lancet Regional Health - Europe (2022)

Population health has stagnated or is declining in many high-income countries. We analysed whether nationally administered austerity cuts in England were associated with prevalence of multimorbidity (individuals with two or more long-term conditions) and health-related quality of life.We conducted an observational, longitudinal study on 147 local authorities in England. We examined associations of changes in spending over time (2009/10-2017/18), in total and by budget line, with (i) prevalence of multimorbidity, 2+ conditions (2011/12-2017/18), and (ii) health-related quality of life (EQ-5D-5L) score (2012/13-2016/17). We estimated linear, log-log regression models, incorporating local authority fixed-effects, time-varying demographic and socio-economic confounders, and time trends.All local authorities experienced real spending cuts, varying from 42% (Barking and Dagenham) to 0·3% (Sefton). A 1% cut in per capita total service expenditure was associated with a 0·10% (95% CI 0·03 to 0·16) increase in prevalence of multimorbidity. We found no association (0·003%; 95% CI -0·01 to 0·01) with health-related quality of life. By budget line, after controlling for other spending, a 1% cut in public health expenditure was associated with a 0·15% (95% CI 0·11 to 0·20) increase in prevalence of multimorbidity, and a 1% cut in adult social care expenditure was associated with a 0·01% (95% CI 0·002 to 0·02) decrease in average health-related quality of life.Fiscal austerity is associated with worse multimorbidity and health-related quality of life. Policymakers should consider the potential health consequences of local government expenditure cuts and knock-on effects for health systems.Medical Research Council.
Dynamic circulating tumor DNA (ctDNA) in monitoring trastuzumab deruxtecan (TDXd) activity for patients (pts) with advanced breast cancer: Preliminary results of a feasibility study.
Authors: Elena Giordani, Antonella Palazzo, Angelo Minucci, Francesco Pavese, Ida Paris, Elisa De Paolis, Elena Ricciardi, Armando Orlandi, Sergio Pannunzio, Giordana Tiberi, Luisa Carbognin, Emilio Bria, Diana Giannarelli, Giovanni Scambia, Patrizio Giacomini, Alessandra Fabi
Journal: Journal of Clinical Oncology (2022)

1046 Background: Trastuzumab Deruxtecan (TDXd), a novel antibody-drug conjugate (ADC) that combines trastuzumab with a topoisomerase I inhibitor, has recently demonstrated high efficacy in HER2-overexpressing breast cancer after trastuzumab failure. Resistance to TDM1 have recently suggested to be dynamically associated with distinct circulating ctDNA species ( Allegretti et al, Mol Cancer 2021). A prospective study aiming to evaluate the feasibility of Liquid Biobsy (LB) in monitoring ctDNA in pts receiving TDXd in the national Expanded Access Program was conducted. Methods: In this prospective study, LB for ctDNA analysis (evaluating ‘ per pt’ ctDNA species and Variant Allelic Frequencies, VAF) was performed using 52-gene targeted NGS panel, in patients who progressed after two or more prior anti-HER2-based regimens and candidates to TDXd (3-weekly 5.4 mg/kg). This preliminary analysis reports data referring to Time-0 (T0) and T6 (cycle 6) assays. Results: From April 2021, LBs were collected for 14 pts and to date 8 are evaluable for LB. Median pts’ age was 59 yrs (range 38-72) and median number of previous anti-HER2 lines was 6 (2-11); 4 pts had Pertuzumab/Trastuzumab plus taxane as first-line and all pts received TDM-1. Median cycles of TDXd administered was 7.5 (1-10). At T0, 5/8 pts had at least one detectable ctDNA specie, and the remaining 3 developed at least one ctDNA at T6. ctDNA species and VAFs ranged from 1 to 5, and A0.1% to 68.94%, respectively. Decreases and increases were observed simultaneously in the same pt. The former varied from marginal to drastic, whereas the latter were invariably below 0.5% in VAFs. ctDNA monitoring was possible in 8/8 pts and at T6 ctDNA progression was detectable in 5/8 pts. Two pts displayed multiple HER2 copy number variations. Conclusions: The early results of this study suggest that considerable ctDNA burden, marked clonal complexity, and variable clonal response to TDXd can be found in pretreated HER2 positive patients, who progressed after antiHER2 therapies. Although the very small sample, this complex tumor evolution is surprising in light of the bystander payload effect of TDXd.
Transcriptomic analysis and comparative characterization of rat H9C2, human AC16 and murine HL-1 cardiac cell lines
Authors: Z Gulyas-Onodi, T Visnovitz, A Koncz, B Varadi, B Agg, B Kiss, A Makkos, NR Nagy, VE Toth, P Leszek, A Gorbe, Z Giricz, EI Buzas, P Ferdinandy, ZV Varga
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – EU funding. Main funding source(s): European Union's Horizon 2020 research and innovation programme National Research, Development and Innovation Fund of Hungary Background Cardiac cell lines and primary cell cultures are widely used to model various cardiovascular diseases in vitro. Despite the increasing number of publications using these models, limitations of these cell lines are still undetermined. Purpose The aim of our study was to compare the most commonly used cardiac cell lines to primary cultures and to mature cardiac tissues by transcriptomic analysis and morphological characterization. Methods H9C2 (rat), AC16 (human) and HL-1 (mouse) cardiac cell lines were differentiated towards a phenotype more resembling cardiomyocytes, by methods most widely used in the literature, and cells were harvested at stages of proliferation and differentiation. Whole left ventricular tissue, neonatal primary cardiac myocytes isolated from mice and rats, or human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM) were applied as references. Transcriptome analysis and immunocytochemical detection of cardiac structural proteins were performed on all cell models. Results RNA expression of cardiac markers (e.g. Tnnt2, Ryr2, Tnni3) was markedly lower in cell lines compared to primary cells or hiPSC-CM and adult tissue controls. Differentiation procedures induced a significant increase in cardiac- and decrease in embryonic markers in AC16 and H9C2 lines; however, the overall expression pattern of investigated genes in all cell lines showed significant differences in comparison to corresponding myocardium or primary cultures. Immunocytochemistry confirmed low expressions of structural protein alpha-actinin and troponin I in cell lines. Conclusion Expression patterns of cardiomyocyte markers and mRNA profile indicates low-to-moderate similarity of cell lines to primary cells/cardiac tissues regardless the differentiation protocol used. These limitations should be taken into account while choosing cells as in vitro platforms to model cardiomyocytes and cardiovascular diseases.
OTHR-24. Impact of physical activity on postural stability and coordination in children with posterior fossa tumor: randomized control phase III trial
Authors: Mahmoud Usama, Faten H Abdelaziem, Wafaa M Rashed, Eslam Maher, Mohamed El Beltagy, Wael Zekri
Journal: Neuro-Oncology (2022)

Abstract BACKGROUND: Posterior fossa tumor is a type of brain tumor that is located at the borders of both the brain stem and cerebellum. The cerebellum is the brain region in charge of balance and coordination. Pediatric patients diagnosed with posterior fossa tumor have been reported to fall frequently. OBJECTIVES: The aim of this study is to investigate the effectiveness of balance and coordination training in these children. METHODS: This randomized control clinical trial was carried out between September 2020 and April 2021 at Children’s Cancer Hospital-57357. The inclusion criteria of the participants were - patients with posterior fossa tumor in maintenance phase and, age between 5-12 years. The study participants were randomly assigned into three groups: Group I/Control group: they received Pilates core stability exercises program, Group II/Balance group: They received the same program plus HUMAC balance program, and Group III/Coordination group: They received the same program plus coordination exercises of BOT-2. Descriptive statistics for patients’ characteristics were reported as medians and interquartile ranges for quantitative variables, frequencies, and percentages for qualitative ones. Significance level of P value was at &amp;lt;0.05. RESULTS: Sixty children including 38 boys and 22 girls were enrolled in this study. In all three groups, postural stability and coordination improved significantly in terms of modified clinical test of sensory integration of balance, center of pressure, limits of stability, bilateral coordination, and upper-limb coordination.CONCLUSION: The current study supports the value of adding postural stability and coordination training to the physiotherapy plan for children with posterior fossa tumor. Clinical trial information: RCT no#NCT04528316. Keywords: Posterior fossa tumor, Children, HUMAC, BOT-2, Postural stability, Balance, Coordination.
A multiple centers real-world study of regorafenib treatment modalities in Chinese metastatic colorectal cancer patients.
Authors: Xia Fen Li, Huiyan Luo, Zhiqiang Wang, Jian Xiao, Jianjun Peng, Zi-xian Wang, Xiaohui Zhai, Rui-hua Xu
Journal: Journal of Clinical Oncology (2022)

e15543 Background: To evaluate the efficacy and safety of different treatment modalities of regorafenib in patients with previously treated metastatic colorectal cancer (mCRC) in the real-world setting. Methods: Individual patient data were retrieved from three leading oncology centers in China from January 2016 to March 2021. The primary endpoint was progression-free survival (PFS), and secondary endpoints were overall survival (OS) and safety. Results: The characteristics of patients who received treatment are shown in the table. Twenty-one patients received regorafenib combined with capecitabine as the second-line treatment for those who cannot visit hospital for their chemotherapies because of the COVID-19 pandemic. The median PFS and median OS were 8 (95% CI 4.36 - 11.00) months and 26.9 (95%CI 20.54 -NR) months. 101 patients received regorafenib and 69 patients received regorafenib plus immune checkpoint inhibitor (ICIs) as third or higher line treatment, the overall response was 4.1%(7/170), including one complete response. Patients combined with ICIs have longer PFS than those with regorafenib monotherapy (median PFS = 3.3 versus 2.1 months; p = 0.01). Starting dose was 80、120 and 160 mg in 64、40 and 39 patients, respectively. Dose reduction was observed in 43.3% (39/79) of patients receiving 120 and 160 mg as the initial dose. Conclusions: Different treatment modalities of regorafenib all showed promising efficacy and safety in the treatment of mCRC. Regorafenib combination is better than regorafenib monotherapy. Regorafenib combined with capecitabine provided a new treatment strategy during the epidemic but requires further investigation. Key words:Colorectal cancer; Regorafenib; Immune check point inhibitors; Real world[Table: see text]
Osteoradionecrosis in head and neck cancer patients: Risk factors and comparison of grading systems.
Authors: Junhyung Lee, Amr El-Maghrabi, Sareh Keshavarzi, Wei Xu, Shao Hui Huang, John Waldron, John Kim, Jolie Ringash, Ezra Hahn, John Cho, Scott Victor Bratman, Lawson Eng, John R de Almeida, David Paul Goldstein, Jonathan Crawford Irish, Douglas Brian Chepeha, Andrew J. Hope, Michael Glogauer, Erin Watson, Ali Hosni
Journal: Journal of Clinical Oncology (2022)

e18057 Background: We aimed to identify the incidence and risk factors for osteoradionecrosis (ORN) in head and neck cancer (HNC) patients. We also compared frequency of severity scores across different ORN grading systems. Methods: Retrospective review was conducted for HNC patients who were managed at our institution (2011-2018) with curative-intent definitive, pre- or post-operative intensity-modulated radiation therapy (IMRT) with 45Gy, and underwent pre-IMRT dental evaluation. Jaw ORN was defined based on: 1) clinical signs (exposed bone, bone spicules, sequestra, infection and fistula), 2) radiological finding (abnormal bone pattern, radiographic sequestra and pathological fracture), and 3) treatment required and response to therapy, either conservative (chlorhexidine rinse, antibiotics, PENTOCLO, and hyperbaric oxygen) or surgical (sequestrectomy, debridement, and jaw resection). ORN events were retrospectively graded using 6 different grading systems. Pre-IMRT periodontal condition (PC) was classified by universal multi-dimensional staging system based on number of teeth and bone loss (stages 0 to IV). Multivariable analysis (MVA) using logistic regression was applied to identify risk factors of ORN. Results: A total of 2735 HNC patients were included; median age 61 years, 30% (n = 807) current/ex-smokers, 72% (n = 1914) had moderate to severe PC (stage II-IV), 53% (n = 1459) oral cavity/oropharynx (OC/OP) primary tumor. The median IMRT dose was 70Gy/35 fractions, 43% (n = 1170) received concurrent chemotherapy, and 37% (n = 1006) underwent surgery. A total of 227 patients (8.3%) developed ORN. There was discrepancy in different grading system for capturing and reporting the degree of severity (i.e. grade) of ORN (table). On MVA, risk factors for ORN were: current/ex-smoker (OR 1.5, 95% CI: 1.12-2, p&lt; 0.01), stage II-IV PC (OR 1.7, 95% CI: 1.17-2.36, p&lt; 0.01), primary OC/OP tumor (OR 4.4, 95% CI: 3.08-6.29, p&lt; 0.001], and IMRT dose prescription ≥60Gy (OR 3.5, 95%CI: 1.11-11.33, p&lt; 0.01). Conclusions: ORN is relatively uncommon in HNC patients, however it can be under-reported by different grading systems. Risk factors for ORN were: smoking history, pre-IMRT poor PC condition, OC/OP primary tumor, and higher dose (≥60Gy) IMRT.[Table: see text]
Children with tics can be helped by a new online treatment
Authors: Helen Saul, Deniz Gursul, Jemma Kwint, Charlotte Hall, Chris Hollis
Journal: BMJ (2022)

The study Hollis C, Hall CL, Jones R, et al. Therapist supported online remote behavioural intervention for tics in children and adolescents in England (ORBIT): a multicentre, parallel group, single-blind, randomised controlled trial. Lancet Psychiatry 2021;8:P871-82.
OTHR-45. Kids First Variant WorkBench: application to germline genomic discoveries in the Children's Brain Tumor Network
Authors: Yiran Guo, Jeremy Costanza, Christophe Botek, Miguel Brown, David Higgins, Yuankun Zhu, Bailey Farrow, Allison Heath, Adam Resnick, Vincent Ferretti
Journal: Neuro-Oncology (2022)

Abstract The Gabriella Miller Kids First Pediatric Research Program (Kids First) aims at facilitating researchers to uncover new insights into the biology of childhood cancer (CC) and structural birth defects (SBD). Kids First has two initiatives, i) whole genome sequencing of biospecimens from families with CC/SBD, and ii) establishing Kids First Data Resources. Kids First Data Resource Center developed the Kids First Data Resource Portal (KFDRP), a centralized platform to search, view, analyze, and identify currently accessible data from both Kids First and collaborative cohorts, incorporating omics and phenotypic information of 30 studies and 26,300 participants. A recently released KFDRP component is Variant WorkBench (VWB), enabling users to query, mangle, analyze and visualize genomic variants from participating cohorts, with the Children’s Brain Tumor Network (CBTN) being one of the cohorts. VWB supports programming languages such as Python, Spark, SQL and R for in-depth analysis in Apache Zeppelin notebooks. In addition to variant calls and phenotypic information, VWB hosts rich external variant annotations in the public domain, such as Cancer Hotspots, COSMIC and ClinVar. Users can also load additional databases (e.g. Human Gene Mutation Database/HGMD) within a notebook, import custom datasets as temporary query tables, export analysis outputs to local drives, visualize analysis results in multiple chart styles, display local figures, and save notebooks for sharing, further use and Cavatica projects. In an effort to screen tier 1 genes (n=578) from the most recent Cancer Gene Census provided by COSMIC in CBTN, we identified ~127,500 germline variants that are both rare and damaging, or that are already cataloged in the most recent version of ClinVar/HGMD. The whole process took less than one hour which is much faster than conventional methods. VWB enables efficient genomic variant analysis and discoveries in pediatric neuro-oncology research with advanced big data technology.
Crucial functions of alpha-actinin 2 in the embryonic heart
Authors: K Gehmlich, A Jiang, K Wadmore, C Hooper, G Douglas, E Ehler, S Broadway-Stringer, J Kalisch-Smith, D Sparrow, M Gautel, B Davies, H Watkins
Journal: Cardiovascular Research (2022)

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): Wellcome Trust; British Heart Foundation Background/Introduction Alpha-actinin is an integral protein of the Z-discs in heart and skeletal muscle cells, with important structural and signalling functions. Missense variants in alpha-actinin can cause inherited conditions, e.g. myopathies and cardiomyopathies. The underlying disease mechanisms are still unknown. Purpose In order to study the disease mechanisms of an alpha-actinin missense variant, which is known to cause Hypertrophic Cardiomyopathy in human patients, a mouse model was generated. Methods Mice carrying the alpha-actinin missense variant were generated by CRISPR-Cas9 genome editing. The heterozygous adult mice carrying the alpha-actinin variant were characterised by echocardiography and quantitative PCR. Hearts of homozygous embryos were analysed at E15.5 by high-resolution episcopic microscopy (HREM). Results Mice carrying a single copy of the missense variant were viable and had normal appearance. Adult heterozygous mice showed no signs of cardiomyopathy on echocardiography. However, mature male mice displayed molecular signs of cardiomyopathy, such as induction of the fetal gene programme at transcript level. The attempt to generate adult mice homozygous for the variant failed: 9 breeding pairs produced 18 litters with 83 weaned pups, but no homozygous offspring. Embryonic lethality was confirmed and E15.5 was the latest stage homozygous pups were reliably found to be viable. At this timepoint, genotype distribution was within the expected Mendelian ratios. HREM of the hearts at this stage revealed increased right ventricular chamber size and decreased left atrial size, when compared to wildtype littermates. Membranous ventricular septal defects were observed in 3 out of 8 homozygous hearts. Further these embryos displayed aortic stenosis and dysplasic leaflets of the pulmonary valve. Conclusions Heterozygous adult mice only displayed sub-clinical signs of disease. In contrast, the missense variant is embryonic lethal in the homozygous setting and leads to a range of morphological abnormalities in E15.5 hearts. Future work will identify how altered functions of alpha-actinin cause these changes.
Effects of exercise during adjuvant chemotherapy for breast cancer on long-term cardiotoxicity.
Authors: Willeke Naaktgeboren, Martijn M. Stuiver, Wim H. van Harten, Neil K Aaronson, Jessica Scott, Gabe S. Sonke, Elsken Van Der Wall, Miranda Velthuis, Tim Leiner, Arco J. Teske, Anne Maria May, Wim G Groen
Journal: Journal of Clinical Oncology (2022)

12081 Background: A common conception is that exercise training is cardioprotective for patients with breast cancer receiving adjuvant chemotherapy, but evidence to support this assertion is limited. This study aims to evaluate the effect of exercise training during adjuvant chemotherapy for breast cancer on long-term structural and functional cardiac outcomes. Methods: This is a follow-up study of two previously performed randomized studies in breast cancer patients; the PACT (N = 204) and PACES (N = 230) study. Cardiac outcomes, including extracellular volume fraction (ECV), left ventricular ejection fraction (LVEF) on cardiac MRI and global longitudinal strain (GLS) on echocardiography, were evaluated in patients allocated to moderate-to high-intensity exercise and non-exercise controls using linear and logistic regression models, adjusted for relevant confounders. Additionally, we explored the influence of self-reported PA during chemotherapy on cardiac outcomes, regardless of treatment allocation. Results: In total, 185 breast cancer survivors were included (mean age 58.9±7.8 years, mean time since treatment 8.5±1.1 years). Mean ECV was 25.3±2.5 in the control group and 24.6±2.8 in the exercise group. Mean LVEF was borderline normal in both (54.6±4.9 and 53.0±7.8) with an LVEF &lt; 50% of 17.1% and 27.8% in control and exercise group, respectively. Compared to control, no significant effect of exercise during chemotherapy on ECV (β = -0.61, 95%CI: -1.55;0.32) or on abnormal ECV (OR = 0.80, 95%CI: 0.26;2.45) was found. Native T1 was statistically significantly lower in the exercise group compared to control (β = -16.75%CI: -31.5 ;-1.93). The odds of having an abnormal native T1 appeared lower in the exercise group (OR 0.58, 95%CI: 0.28;1.17). We found no benefit of exercise for LVEF or GLS (β = -1.82, 95%CI: -4.06;0.42 and β = 0.21, 95%CI: -0.87;1.28), nor on the likelihood of having an abnormal LVEF or GLS (OR = 1.78, 95%CI: 0.79;4.16); OR = 1.21, 95%CI: 0.56;2.63), respectively. Higher self-reported physical activity levels during chemotherapy tended to be associated with better cardiac outcomes. Conclusions: Exercise training during chemotherapy was not associated with long-term cardioprotection in patients with early-stage breast cancer. The high prevalence of cardiac abnormalities years post-chemotherapy suggests the need to include cardiac assessment in long-term follow-up programs for breast cancer survivors and calls for more research on cardioprotective measures during adjuvant chemotherapy, including alternative exercise dosing regimens and pharmacological adjuncts. Clinical trial information: NTR7247.